Risk Management Plan Summary - swissmedic.ch€¦ · RMP version 1.5 Eluxadoline Part VI: ... 1% in...

Risk Management Plan Summary

Truberzi®

Eluxadoline

75 mg & 100 mg

Film-coated tablets

Document Version: 1.0

Document Date: 06.04.2018

Based on EU RMP version 1.5

Marketing Authorisation Holder: Allergan AG, Puls 5, Hardturmstrasse 11,

8005 Zürich

Disclaimer: The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier

for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and

explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or

minimize them.

The RMP summary of Truberzi is a concise document and does not claim to be exhaustive. As the RMP is an

international document, the summary might differ from the product information «Arzneimittelinformation /

Information sur le médicament» approved and published in Switzerland, e.g. by mentioning risks occurring in

populations or indications not included in the Swiss authorization.

Please note that the reference document which is valid and relevant for the effective and safe use of Trubzeri

in Switzerland is the «Arzneimittelinformation / Information sur le médicament» (see www.swissmedicinfo.ch)

approved and authorized by Swissmedic. Allergan AG is fully responsible for the accuracy and correctness of

the content of the published summary RMP of Truberzi.

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RMP version 1.5 Eluxadoline

Part VI: Summary of the risk management plan by product VI.1 Elements for summary tables in the European Public Assessment Reports (EPAR) VI.1.1 Summary table of Safety concerns

Summary of safety concerns

Important identified risks Decreased GI motility shown as constipation SO spasm

Pancreatitis Hepatic enzyme elevations associated with biliary-

type pain Important potential risks Potential complications of decreased GI motility (e.g.

serious FI, obstruction, ileus, secondary bowel ischemia, intestinal ulceration/perforation, or TM) Pancreatitis independent from SO spasm Asthma exacerbation Abuse Use in patients ≥65 years of age CNS effects as a result of extended systemic exposure in patients with hepatic impairment or concomitant treatment with OATP1B1 inhibitors

Missing information Use in the paediatric population Use in pregnancy and lactation Use in patients with renal impairment Use in patients of ethnic origin other than whites Use in patients with impaired intestinal barriers (IBD and Coeliac Disease) Drug-drug interactions with drugs metabolized by CYP1A2 or 3A4/5

VI.1.2 Table of on-going and planned studies in the Post-authorisation PV Development Plan Study/activity Type, title and category (1-3)

Objectives Safety concerns addressed

Status (planned, started)

Date for submission of interim or final reports (planned or actual)

Renal impairment study (category 3) - A Single-Dose, Open-Label, PK Study of Eluxadoline in Healthy Subjects with

To assess the PK, safety and tolerability profiles of eluxadoline following single-dose oral administration in male and female patients with severely impaired renal function compared with matched

Use in patients with renal impairment

Planned Planned Submission of final study report 9 months after approval

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Study/activity Type, title and category (1-3)




Normal Renal Function and Patients with Severely Impaired Renal Function multicentre study

healthy subjects with normal renal function.

In-vivo drug-drug-interaction midazolam

Conduct an in-vivo drug-drug-interaction study to evaluated eluxadoline as a potential time dependent inhibitor of Cytochrome P450 3A4 with the substrate midazolam.

Drug-drug interactions with drugs metabolized by CYP1A2 or 3A4/5

Planned submission of final study report 9 months after approval

A study to evaluate the potential for eluxadoline to induce CYP3A4 and 1A2 in vitro using human hepatocytes

Conduct a study to evaluate the potential for eluxadoline to induce CYP3A4 and 1A2 in vitro using human hepatocytes.


Planned Submission of final study report 6 months after approval

DUS (category 3)

Define the compliance of health care providers to eluxadoline contraindications (i.e., history of chol-ecystectomy, pancreatitis or sphincter of Oddi dis-ease) over time.

SO spasm Pancreatitis Hepatic

enzyme elevations associated with biliary-type pain

Planned Submission of first draft of protocol 3 months after ap-proval

VI.1.3 Summary of post authorisation efficacy development plan The applicant did not conduct any post-authorisation efficacy studies and none are planned. VI.1.4 Summary table of RMMs Safety concern Routine RMMs Additional

RMMs

Decreased GI motility (Proposed) text in SmPC Not required

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Safety concern Routine RMMs Additional RMMs

shown as constipation (Important Identified risk)

Section 4.3 Contraindications:

A history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction. These patients may be at risk for severe complications of bowel obstruction.

Section 4.4 Special warnings and precautions for use

Constipation

There is a potential for increased risk of constipation when taking eluxadoline. If patients develop severe constipation for a duration of more than 4 days, they should be instructed to stop eluxadoline and seek medical attention.

Risk of constipation with eluxadoline in patients with other IBS subtypes is unknown, but may be increased. Caution should be exercised when administering eluxadoline in IBS patients whose bowel habits vary over time.

Section 4.5 Interaction with other medicinal products and other forms of interaction

Medicinal products that cause constipation

Although no direct drug-drug interactions have been demonstrated, chronic use of loperamide with eluxadoline should be avoided as this may increase the risk of constipation. The use of eluxadoline with other medicinal products that may cause constipation (for example anticholinergics, opioids etc) should be also avoided.

Section 4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions (incidence of >5%) reported were constipation (7% and 8% of patients receiving 75 mg and 100 mg respectively), nausea (8% and 7% of patients receiving 75 mg and 100 mg

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respectively) and abdominal pain (6% and 7% of patients receiving 75 mg and 100 mg respectively).

Tabulated list of adverse reactions

Gastrointestinal disorders

Constipation – Common

Description of selected adverse reactions

Constipation

Approximately 50% of constipation events occurred within the first 2 weeks of treatment.

Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg eluxadoline and there were no serious com-plications of constipation related to eluxadoline use in pivotal studies. 1 % of patients receiving 75 mg and 2% of patients receiving 100 mg discontinued treatment or temporarily suspended dosing secondary to constipation, respectively, compared to <1% of patients treated with placebo. Patients should be instructed to stop the medicinal product and seek medical attention if they develop severe constipation for more than 4 days.

SO spasm • Pancreatitis • Hepatic enzyme

elevations associated with biliary-type pain

(Important Identified risk)

(Proposed) text in SmPC Section 4.3 of the SmPC states: Contraindications • Alcoholism, alcohol abuse, alcohol addiction or chronic or acute excessive alcohol use. These patients are at increased risk for acute pancreatitis. • Known or suspected biliary duct obstruction or sphincter of Oddi disease or dysfunction. These patients are at increased risk for sphincter of Oddi spasm. • Patients without a gallbladder ( e.g. due to cholecystectomy or agenesis). These patients are also at increased risk for sphincter of Oddi spasm • A history of pancreatitis; or known or suspected structural diseases of the pancreas, including pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis.

Not required

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Section 4.4 of the SmPC states: Warnings and Precautions for Use Sphincter of Oddi Spasm Given the mu opioid receptor agonism of eluxadoline there is a potential for increased risk of sphincter of Oddi spasm, resulting in pancreatitis or hepatic enzyme elevation associated with acute abdominal pain (eg, biliary-type pain) in patients taking eluxadoline, especially in patients without a gallbladder. Patients with known or suspected sphincter of Oddi disease or dysfunction and/or biliary tract or pancreatic disease, including a history of pancreatitis, and those who have had a cholecystectomy or are missing a gallbladder due to other reasons, must not receive this medicinal product. Truberzi Patients should be instructed to stop the treatment and seek medical attention if they experience symptoms suggestive of sphincter of Oddi spasm such as acute worsening of abdominal pain (e.g. acute epigastric or biliary [i.e., right upper quadrant] pain) that may radiate to the back or shoulder, with or without nausea and vomiting. Eluxadoline should not be restarted in patients who developed biliary duct obstruction or sphincter of Oddi spasm while taking eluxadoline. Section 4.8 of the SmPC: Summary of the safety profile Serious adverse reactions of pancreatitis (0.2% and 0.3% of patients receiving 75 mg and 100 mg respectively) and sphincter of Oddi spasm (0.2% of patients receiving 75 mg and 0.8% of patients receiving 100 mg) may also occur. Sphincter of Oddi spasm In clinical studies, events of sphincter of Oddi spasm manifested as elevated hepatic enzymes associated with abdominal pain in 8 patients, pancreatitis in 1 patient, and abdominal pain with lipase elevation less than 3 times the upper limit of normal in 1 patient. 80% (8/10) of sphincter of Oddi spasm events presented within the first week of treatment. All events resolved upon discontinuation of Truberzi, with symptoms typically improved by the following day. All events of sphincter of

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Oddi spasm occurred in patients without a gallbladder. Therefore, eluxadoline is contraindicated in this population as well as in those with previous biliary tract problems. The occurrence of such events in patients with an intact biliary tract cannot be excluded Pancreatitis All pancreatic events, whether or not associated with sphincter of Oddi spasm, were retrospectively evaluated as mild, indicating an absence of organ failure and local or systemic complications. All pancreatic events resolved with lipase normalization upon discontinuation of eluxadoline, with 80% (4/5) resolving within 1 week of treatment discontinuation Tabulated list of adverse reactions Gastrointestinal disorders Uncommon: Sphincter of Oddi spasm, Pancreatitis Other routine RMMs Prescription only medicine

Complications of decreased GI motility (serious FI, obstruction, ileus, secondary bowel ischemia, intestinal ulceration/perforation, TM) (Important Potential risk)

(Proposed) text in SmPC Section 4.3 of the SmPC: Contraindications A history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction. These patients may be at risk for severe complications of bowel obstruction. Section 4.4 of the SmPC: Warnings and Precautions for Use Constipation: There is a potential for increased risk of constipation when taking eluxadoline. If patients develop severe constipation for a duration of more than 4 days, they should be instructed to stop eluxadoline and seek medical attention. Risk of constipation with eluxadoline in patients with other IBS sub-types is unknown, but may be increased. Caution should be exercised when administering eluxadoline in IBS patients whose bowel habits vary over time. Section 4.5 of the SmPC: Interaction with other medicinal products and other forms of interaction Medicinal products that cause constipation Although no direct drug-drug interactions have

Not required

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been demonstrated, chronic use of loperamide with eluxadoline should be avoided as this may increase the risk of constipation. The use of eluxadoline with other medicinal products that may cause constipation (for example anticholinergics, opioids etc.) should also be avoided. Section 4.8 of the SmPC: The most common adverse reactions (incidence of >5%) reported were constipation (7% and 8% of patients receiving 75 mg and 100 mg respectively), nausea (8% and 7% of patients receiving 75 mg and 100 mg respectively) and abdominal pain (6% and 7% of patients receiving 75 mg and 100 mg respectively). Constipation Approximately 50% of constipation events occurred within the first 2 weeks of treatment Rates of severe constipation were less than 1% in patients receiving 75 mg and 100 mg eluxadoline and there were no serious complications of constipation related to eluxadoline use in pivotal studies. 1 % of patients receiving 75 mg and 2% of patients receiving 100 mg discontinued treatment or temporarily suspended dosing secondary to constipation, respectively, compared to <1% of patients treated with placebo. Patients should be instructed to stop the medicinal product and seek medical attention if they develop severe constipation for more than 4 days. Tabulated list of adverse reactions Gastrointestinal disorders Common: Constipation Other routine RMMs Prescription only medicine

Pancreatitis independent from SO spasm (Important Potential risk)

(Proposed) text in SmPC

Section 4.3 Contraindications

A history of pancreatitis; or known or suspected structural diseases of the pancreas, including pancreatic duct obstruction. These patients are at increased risk for acute pancreatitis.

None

8



Section 4.4 Special warnings and precautions for use

Pancreatitis

There is a potential for increased risk of pancreatitis, not associated with sphincter of Oddi spasm, when taking eluxadoline. All patients should be instructed to avoid chronic or acute excessive alcohol use while taking eluxadoline Patients should be monitored for new or worsening abdominal pain that may radiate to the back or shoulder, with or without nausea and vomiting. Patients should be instructed to stop the medicinal product and seek medical attention if these symptoms develop while taking eluxadoline.

Section 4.8 Undesirable effects

Summary of the safety profile

Serious adverse reactions of pancreatitis (0.2% and 0.3% of patients receiving 75 mg and 100 mg respectively) and sphincter of Oddi spasm (0.2% of patients receiving 75 mg and 0.8% of patients receiving 100 mg) may also occur.

Tabulated list of adverse reactions

Gastrointestinal disorders

Pancreatitis – Uncommon

Pancreatitis

Additional cases of pancreatitis not associated with sphincter of Oddi spasm were reported in clinical studies. Of the 5 cases reported, 3 were associated with excessive alcohol intake, 1 was associated with biliary sludge, and in one case the patient discontinued eluxadoline 2 weeks prior to the onset of symptoms.

All pancreatic events, whether or not associated with sphincter of Oddi spasm, were retrospectively evaluated as mild, indicating an absence of organ failure and local or systemic

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complications. All pancreatic events resolved with lipase normalization upon discontinuation of eluxadoline with 80% (4/5) resolving within 1 week of treatment discontinuation.

Other routine RMMs

Prescription only medicine Asthma exacerbation (Important Potential risk)

None proposed None

Abuse (Important Potential risk)

Proposed text in SmPC Drug dependence and potential for abuse Based on the physical-chemical and biopharmaceutical properties (very low oral bioavailability), eluxadoline is expected to have minimal abuse or dependence liability. Other routine RMMs Prescription only medicine

None

Use in patients ≥65 years of age (Important Potential risk)

Proposed text in SmPC Section 4.2 of the SmPC: Posology and method of administration The recommended dose is 200 mg daily (one 100 mg tablet twice daily). For patients who are unable to tolerate the 200 mg daily dose (one 100 mg tablet, twice daily) the dose can be lowered to 150 mg daily (one 75 mg tablet twice daily). Elderly In principle, general dose recommendations also apply to patients aged 65 years and above. However, given the potential for increased sensitivity to experience undesirable effects, it may be considered to initiate eluxadoline treatment in a dosage of 150 mg daily (one 75 mg tablet twice daily). If this dosage is well tolerated, but not sufficiently effective, dosage may subsequently be increased to 200 mg daily (one 100 mg tablet twice daily). Section 4.4 of the SmPC: Warnings and Precautions for Use Special population Elderly Overall there was an increased frequency of adverse events reported for patients aged 65 years or greater in the clinical studies. However, patients 65 years of age and older, treated with the 75-mg dose twice daily have experienced a reduced rate of serious adverse events as well as adverse events leading to

None

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discontinuation compared to patients treated with 100mgdose twice daily. Therefore, the 75 mg dose twice daily can be considered for this population, but its benefit risk ratio should be periodically assessed in the context of their symptoms severity. Section 4.8 of the SmPC: Elderly Of 1,795 IBS-D patients who were enrolled in clinical studies of eluxadoline and assigned to 75 mg or 100 mg twice daily, 139 (7.7%) were at least 65 years of age, while 15 (0.8%) were at least 75 years old. There was an overall increased frequency of adverse events in the older population compared to patients <65 years which was comparable across all treatment groups, including placebo. The frequency of serious adverse events, gastrointestinal events, and events leading to discontinuation tended to be lower for the 75 mg dose compared to the 100 mg dose. Therefore, in this population, the 75 mg dose twice daily can be used. Section 5.2 of the SmPC: Specific populations Age and gender Given eluxadoline’s local action in the GI tract, low Foral and lack of metabolism, prospective clinical studies regarding differences in age, body mass index (BMI), ethnicity, and gender were deemed unnecessary. Pharmacokinetic data for healthy volunteers pooled across Phase 1 studies (using the 100 mg single oral dose) and analysed for potential differences based on sex, age, race, and BMI demonstrated no significant differences. Other routine RMMs Prescription only medicine

CNS effects as a result of extended systemic expo-sure in patients with hepatic impairment or concomitant treatment with OATP1B1 inhibitors (Important Potential risk)

Proposed text in SmPC Section 4.3 of the SmPC: Contraindications Hepatic impairment (Child-Pugh Class A-C). These patients are at risk for significantly increased plasma concentrations of eluxadoline. Patients on treatment with potent inhibitors of OATP1B1 (e.g. cyclosporine).Section 4.4 of

None

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the SmPC: Warnings and precautions for use Hepatic impairment Eluxadoline must not be used in patients with a history of or known or suspected hepatic impairment (Child-Pugh Class A-C). Somnolence and sedation

There is a potential for increased risk of somnolence and sedation when taking eluxadoline in patients who may experience increased plasma levels, such as in patients with a genetic predisposition for poor function of OATP1B1 transporter. As patient’s genetic disposition may be unknown, it is recommended that patients be monitored for impaired mental or physical abilities needed to perform potentially hazardous activities such as driving a car or using machines.

Effect of OATP1B1 transporter function variability on plasma levels

The plasma levels in patients with a genetic predisposition for poor function of OATP1B1 transporter are increased, and in these patients a higher rate of adverse events, especially with regard to gastrointestinal events, as well as CNS effects might be expected.

Section 4.5 of the SmPC:

OATP1B1 inhibitors

Co-administration of OATP1B1 inhibitors (cyclosporine, gemfibrozil, antiretrovirals (atazanavir, lopinavir, ritonavir, saquinavir, tipranavir), rifampin) with eluxadoline may increase exposure to eluxadoline. Eluxadoline should not be administered concomitantly with such medicinal products.

Section 5.2 of the SmPC: Hepatic impairment The apparent clearance of eluxadoline is markedly reduced and half-life increases in hepatic-impaired patients. Following single oral

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100 mg dose in subjects with varying degrees of liver impairment and healthy subjects, eluxadoline plasma levels were on average 6-fold, 4-fold, and 16-fold elevated in mild, moderate, and severe hepatic-impaired subjects (Child Pugh Class A, B, C), respectively, while half-life increased 3-5 fold. OATP1B1 inhibitors Eluxadoline is a substrate of the hepatic uptake transporter OATP1B1. Co- administration of eluxadoline with cyclosporine (an OATP1B1 inhibitor) increased eluxadoline exposure by approximately 5- fold. OATP1B1 poor function haplotypes The plasma levels in patients with a genetic predisposition for poor function of OATP1B1 transporter are increased and in these patients a higher rate of adverse events, especially with regard to gastrointestinal events, as well as CNS effects might be expected. Other routine RMMs Prescription only medicine

Use in the paediatric population (Missing information)

(Proposed) text in SmPC Section 4.2 Posology and method of administration Paediatric population The safety and efficacy of eluxadoline in children aged 0 to18 years have not yet been established. No data are available. Section 4.4 Warnings and Precautions for Use Paediatric population Eluxadoline should not be used in children and adolescents as it has not been studied in this population. Other routine RMMs Prescription only medicine

Not required

Use in pregnancy and lactation (Missing information)

(Proposed) text in SmPC Section 4.6 Fertility, pregnancy and lactation Pregnancy There is limited amount of data from the use of eluxadoline in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Truberzi during pregnancy. Breast-feeding

Not required

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It is unknown whether eluxadoline is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of eluxadoline in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Truberzi therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Section 5.3 of the SmPC states: 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development. In rat, eluxadoline was excreted into milk in an approximately dose proportional manner with maximal concentrations less than plasma concentrations. Other routine RMMs Prescription only medicine

Use in patients with renal impairment (Missing information)

(Proposed) text in SmPC Section 4.2 Posology and method of administration Patients with renal impairment The safety and pharmacokinetics of eluxadoline in patients with renal impairment have not yet been established. With the renal route being a minor route of elimination for eluxadoline, no dose adjustment is necessary based on renal function. Section 4.4 Special warnings and precautions for use Renal impairment No data on the pharmacokinetics of eluxadoline in patients with renal impairment are available. Due to minimal absorption and the negligible role for renal elimination, an influence of renal impairment on the plasma levels of eluxadoline is not expected. Section 5.2 Pharmacokinetic properties Renal Impairment Eluxadoline has not been specifically studied in patients who have renal impairment. Given the low oral bioavailability (Foral 1.34%) of eluxadoline and limited renal elimination, renal

Not required

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impairment is not expected to affect clearance of eluxadoline. Other routine RMMs Prescription only medicine

Use in patients of ethnic origin other than whites (Missing information)

None proposed Other routine RMMs Prescription only medicine

None

Use in patients with impaired intestinal barriers (IBD and Coeliac Disease) (Missing information)

None Other routine RMMs Prescription only medicine

None


(Proposed) text in SmPC

Section 4.5 Interaction with other medicinal products and other forms of interaction

CYP3A substrates

Eluxadoline may increase the exposure of co administered medicinal products metabolised by Cytrochrome CYP3A4. Caution should be exercised when administering such products (e.g. midazolam, erythromycin, nifedipine), especially for those with a narrow therapeutic index (e.g. alfentanil, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus). The concentration of these co-administered medicinal products with a narrow therapeutic index or their other pharmacodynamic markers should be monitored when concomitant use with eluxadoline is initiated or discontinued.

Section 5.2 Pharmacokinetic properties

Eluxadoline’s systemic exposure following oral administration is low and is consistent with its local action in the GI tract. The active substance has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Mean plasma elimination half -life is 5 hours with high inter-subject variability. Eluxadoline is primarily cleared as such via the biliary system with the kidney playing a minimal role in elimination. Eluxadoline is not an inducer/inhibitor of major CYP enzymes, however, eluxadoline has some potential for the metabolism based inactivation of CYP3A4.

None

15



It is a substrate and an inhibitor of the hepatic uptake transporter OATP1B1; and a substrate for the hepatic efflux transporter MRP2. Hepatic impairment or coadministration with cysclosporine results in significant increases in plasma concentrations of eluxadoline.

In vitro assessment of drug interactions

In vitro studies indicate that eluxadoline is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2C8 and CYP2D6 at clinically relevant concentrations. CYP2E1 was slightly inhibited (50% inhibitory concentration [IC50] of approximately 20 µM [11 µg/mL]), although this is not expected to result in any clinically meaningful interactions. In vitro studies in liver microsomes showed that eluxadoline is not an inhibitor of CYP3A4 at clinically relevant concentrations, but in intestinal microsomes, eluxadoline inhibited CYP3A4 with a Ki of 450 µM (256 µg/mL). Potentially high (up to 700 µM) eluxadoline concentrations in gut may affect the pharmacokinetic of concomitantly administered CYP3A4 substrates.

VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Truberzi is used to treat irritable bowel syndrome with diarrhoea (called “IBS-D”) in adult patients. The main symptoms include abdominal pain and/or discomfort, diarrhoea, urgent bowel movements. IBS-D is not a life-threatening condition. It is a chronic relapsing disorder characterized by recurrent symptoms of variable severity. IBS is a common gut disorder. The percentage of persons in the general population affected by this condition can go up to 20%, being seen more frequently in women compared to men. The age distribution of affected patients can be broad but most are between 35 and 50 years of age. IBS-D is commonly associated with other medical conditions, such as mental illness (e.g.: depression, anxiety (generalised fear)), various conditions associated with pain (e.g.: CFS, back pain, pelvic pain, headache) or other functional disorders related to the stomach or intestine (e.g.: dyspepsia, cyclic vomiting syndrome). VI.2.2 Summary of treatment benefits The clinical response of Truberzi was demonstrated in two studies over 26 weeks of treatment. Patients that were treated with 75mg and 100mg demonstrated improvement in daily abdominal pain and stool consistency as compared to placebo. Additionally, treatment with 100 mg Truberzi twice daily showed improvement in urgency and stool consistency, and abdominal pain symptoms. Among the subset of patients 65 years of age and older, the 75 mg twice daily dose resulted in larger treatment effects relative to placebo as well as larger

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treatment effects on abdominal pain response, stool consistency response, and global symptom response. VI.2.3 Unknowns relating to treatment benefits In clinical trials, patients under the age of 18 years were not studied and so the effect of Truberzi in these patients is not known. The effect of Truberzi when used in pregnancy or breast-feeding is also not known. In addition the effects of Truberzi in patient with renal impairment, ethnic origin other than whites, patients suffering from diseases that damage the intestinal barrier, and drug-drug interactions with drugs metabolised by certain enzymes in the liver known as CYP1A2 or 3A4/5 are not known. VI.2.4 Summary of safety concerns Important identified risks

Risk What is known Preventability

Decreased GI motility shown as constipation

Truberzi can stimulate opioid receptors along the gut that play a key role in regulating the movement of the gut. Approximately 50% of constipation events occurred within the first 2 weeks of treatment.

Patients with a history of chronic or severe constipation should not take Truberzi Patients should stop taking Truberzi and seek medical attention if they develop severe constipation for a duration of more than 4 days. In addition patients should avoid taking drugs that can cause constipation (e.g., loperamide) at the same time as Truberzi.

Sphincter of Oddi spasm (spasm of a small round muscle in the upper belly) • Pancreatitis (inflammation of the pancreas) • Increase of liver enzymes associated with pain in the upper belly near the stomach

The sphincter of Oddi, a small round muscle in the upper belly, normally lets the digestive juices flow from the liver and pancreas into the intestines. Truberzi may induce spasm of this muscle. If the muscle goes into spasm, the juices do not flow causing pain in the upper belly near the stomach. Pain may begin soon after Truberzi treatment starts. Affected patients might also feel pain on the right side of your belly, or it may feel like it is moving through to their back. Nausea and vomiting could also manifest. Patients who had their gallbladder removed may be at higher risk for having this kind of muscle spasm. The spasm usually goes away when Truberzi treatment is stopped.

Yes, by monitoring for early symptoms. Patients should stop taking Truberzi and seek medical attention immediately if they have new or worsening abdominal pain with or without nausea and vomiting, while taking eluxadoline. Patients who have or may have had disease or dysfunction of the sphincter of Oddi, or a history of pancreatitis, or who do not have a gall bladder should not take Truberzi Likewise patients that suffer from alcohol abuse/addiction are at increased risk for acute pancreatitis and should not take Truberzi.

Important potential risks

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Risk What is known (Including reason why it is considered a potential risk)

Potential complications of decreased GI motility (e.g. decreased motility of the stomach or the bowels, serious faecal impaction (serious cases of hardened faeces accumulated in the rectum), obstruction (blockage in the intestine/bowels), ileus (disruption of the normal propulsive motor activity of the GI tract due to non-mechanical factors), secondary bowel ischemia (compromised blood perfusion to the intestine), intestinal ulceration/perforation, toxic megacolon (non-obstructive dilatation of the colon)).

Patients treated with Truberzi may be at risk of developing complications of decreased motility of the stomach or the bowels. This risk is supported by theoretical mechanisms. Only a very limited number of patients reported this type of reactions during the clinical studies (2 patients) and therefore this risk was classified as potential.

Pancreatitis (inflammation of the pancreas) independent from sphincter of Oddi spasm (spasm of a small round muscle in the upper belly)

Additional cases of pancreatitis not associated with sphincter of Oddi spasm were reported in clinical trials. All pancreatic events, whether or not associated with sphincter of Oddi spasm, were evaluated as mild.

Asthma exacerbation (worsening of asthma)

In some patients who already suffer from asthma, taking Truberzi was shown occasionally to make the asthma worse. Most of these cases of worsening of asthma were mild to moderate.

Abuse Based on the chemical properties and the low intestinal absorption the drug is expected to have minimal abuse or dependence liability.

Use in patients ≥65 years of age

In clinical trials, patients ≥65 years of age experienced more side effects than younger patients. In order to minimise this risk, a lower dose of 75mg twice a day could be considered for these patients.

CNS effects as a result of extended systemic exposure in patients with hepatic impairment or concomitant treatment with OATP1B1 inhibitors (effects on the brain as a result of increased levels of Truberzi in the blood in patients who have impairment of the functioning

Data currently available from a clinical study conducted in patients with impaired liver function indicate that significantly higher concentrations of Truberzi may appear in the blood of these patients after a single dose of 100 mg Truberzi was administered. Patients with liver impairment should not take Truberzi. Co-administration of OATP1B1 inhibitors (cyclosporine, gemfibrozil, antiretrovirals (atazanavir, lopinavir, ritonavir, saquinavir, tipranavir), rifampin) with Truberzi may increase the concentration of eluxadoline in the blood and may

18


Risk What is known (Including reason why it is considered a potential risk)

of their liver or who take certain drugs where there may be an interaction to increase blood levels of Truberzi)

increase the rate of adverse events.

Missing information

Risk What is known

Use in the paediatric population

The safety and efficacy of Truberzi in children aged 0 to 18 years have not yet been established. Truberzi should not be given to children and adolescents less than 18 years old as there is not enough information about its use in this age group. Three studies will be conducted to confirm the safety and efficacy of Truberzi treatment in this group of patients.

Use in pregnancy and lactation

Currently there is limited amount of data from the use of Truberzi in pregnant women. It is unknown whether Truberzi is excreted in human milk. Due to these, Truberzi should not be used whilst pregnant or breast-feeding.


The effect of renal impairment on Truberzi has not been evaluated but it is anticipated that no dose adjustment is necessary based on the renal function. A study will be conducted to confirm the safety and efficacy of Truberzi treatment in this group of patients.

Use in patients of ethnic origin other than whites

Currently there is limited amount of data on the use of Truberzi in patients of ethnic origin other than whites.

Use in patients with impaired intestinal barriers (IBD and Coeliac Disease)

Currently there is limited amount of data on the use of Truberzi in patients with diseases that can damage the integrity of the intestinal wall.

Drug-drug interactions with drugs metabolised by certain enzymes in the liver known as CYP1A2 or 3A4/5

Currently there is limited amount of data on the use of Truberzi in patients taking drugs that are metabolised by CYP1A2 or 3A4/5

VI.2.5 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. The Summary of Product Characteristics and the Package leaflet for Truberzi can be found in the product’s EPAR page. This medicine has no additional risk minimisation measures.

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VI.2.6 Planned post authorisation development plan





Renal impairment study (category 3) - A Single-Dose, Open-Label, PK Study of Eluxadoline in Healthy Subjects with Normal Renal Function and Patients with Severely Impaired Renal Function, multicentre study

To assess the PK, safety and tolerability profiles of eluxadoline following single-dose oral administration in male and female patients with severely impaired renal function compared with matched healthy subjects with normal renal function.


Planned Planned Submission of final study report 9 months after approval

In-vivo drug-drug-interaction midazolam

Conduct an in-vivo drug-drug-interaction study to evaluated eluxadoline as a potential time dependent inhibitor of Cytochrome P450 3A4 with the substrate midazolam.

Drug-drug interactions with drugs metabolised by CYP1A2 or 3A4/5

Planned Submission of final study report 9 months following approval

A study to evaluate the potential for eluxadoline to induce CYP3A4 and 1A2 in vitro using human hepatocytes

Conduct a study to evaluate the potential for eluxadoline to induce CYP3A4 and 1A2 in vitro using human hepatocytes.

Drug-drug interactions with drugs metabolised by CYP1A2 or 3A4/5

Planned Submission of final study report 6 months following approval.

DUS (category 3)

Define the compliance of health care providers to eluxadoline contraindications (i.e., history of chol-ecystectomy,

SO spasm Pancreatitis Hepatic

enzyme elevations associated with

Planned Submission of first draft of protocol 3 months after ap-proval

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pancreatitis or sphincter of Oddi dis-ease) over time.

biliary-type pain

Studies which are a condition of the marketing authorisation None of the above studies are conditions of the marketing authorisation. VI.2.7 Summary of changes to the RMP over time Major changes to the RMP over time Version Date Safety Concerns Comment

1.2 09-06-2016 Important Identified Risks: Decreased GI motility shown as constipation SO spasm

Pancreatitis Hepatic enzyme elevations associated

with biliary-type pain Important Potential Risks: Potential complications of decreased GI motility (e.g. serious FI, obstruction, ileus, secondary bowel ischemia, intestinal ulceration/perforation, or TM) Pancreatitis independent from SO spasm Asthma exacerbation Abuse Use in patients ≥65 years of age CNS effects as a result of extended systemic exposure in patients with hepatic impairment or concomitant treatment with OATP1B1 inhibitors Missing Information: Use in the paediatric population Use in pregnancy and lactation Use in patients with renal impairment Use in patients of ethnic origin other than whites Use in patients with impaired intestinal barriers (IBD and Coeliac Disease)

1.3 12-07-2016 Addition of Drug-drug interactions with drugs metabolised by CYP1A2 or 3A4/5 as Missing Information

1.4 18-07-2016 Addition of DUS 1.5 20-07-2016 PV Plan milestone and timeline changes

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